Clin Infect Dis.-2007-Dellit-159-77

GUIDELINES
Infectious Diseases Society of America and the

Society for Healthcare Epidemiology of America
Guidelines for Developing an Institutional Program
to Enhance Antimicrobial Stewardship
Timothy H. Dellit,1 Robert C. Owens,2 John E. McGowan, Jr.,3 Dale N. Gerding,4 Robert A. Weinstein,5
John P. Burke,6 W. Charles Huskins,7 David L. Paterson,8 Neil O. Fishman,9 Christopher F. Carpenter,10 P. J. Brennan,9
Downloaded from http://cid.oxfordjournals.org/ at IDSA member on February 26, 2016

Marianne Billeter,11 and Thomas M. Hooton12
1
Harborview Medical Center and the University of Washington, Seattle; 2Maine Medical Center, Portland; 3Emory University, Atlanta, Georgia;
4
Hines Veterans Affairs Hospital and Loyola University Stritch School of Medicine, Hines, and 5Stroger (Cook County) Hospital and Rush
University Medical Center, Chicago, Illinois; 6University of Utah, Salt Lake City; 7Mayo Clinic College of Medicine, Rochester, Minnesota;
8
University of Pittsburgh Medical Center, Pittsburgh, and 9University of Pennsylvania, Philadelphia, Pennsylvania; 10William Beaumont Hospital,
Royal Oak, Michigan; 11Ochsner Health System, New Orleans, Louisiana; and 12University of Miami, Miami, Florida
EXECUTIVE SUMMARY and deserves careful oversight and guidance. Given the
association between antimicrobial use and the selection
This document presents guidelines for developing in-
of resistant pathogens, the frequency of inappropriate
stitutional programs to enhance antimicrobial steward-
antimicrobial use is often used as a surrogate marker
ship, an activity that includes appropriate selection,
for the avoidable impact on antimicrobial resistance.
dosing, route, and duration of antimicrobial therapy.
The combination of effective antimicrobial stewardship
The multifaceted nature of antimicrobial stewardship
with a comprehensive infection control program has
has led to collaborative review and support of these
recommendations by the following organizations: been shown to limit the emergence and transmission
American Academy of Pediatrics, American Society of of antimicrobial-resistant bacteria. A secondary goal of
Health-System Pharmacists, Infectious Diseases Society antimicrobial stewardship is to reduce health care costs
for Obstetrics and Gynecology, Pediatric Infectious Dis- without adversely impacting quality of care.
eases Society, Society for Hospital Medicine, and Society These guidelines focus on the development of effec-
of Infectious Diseases Pharmacists. The primary goal tive hospital-based stewardship programs and do not
of antimicrobial stewardship is to optimize clinical out- include specific outpatient recommendations. Although
comes while minimizing unintended consequences of judicious use of antimicrobials is important in out-
antimicrobial use, including toxicity, the selection of patient clinics and long-term care facilities, there are
pathogenic organisms (such as Clostridium difficile), very few data regarding effective interventions, and it
and the emergence of resistance. Thus, the appropriate is unclear which interventions are most responsible for
use of antimicrobials is an essential part of patient safety improvement in these settings.
The population targeted by these guidelines includes
all patients in acute care hospitals. Most of the evidence
Received 3 October 2006; accepted 4 October 2006; electronically published supporting the recommendations in these guidelines is
13 December 2006.
derived from studies of interventions to improve an-
These guidelines were developed and issued on behalf of the Infectious
Diseases Society of America and the Society for Healthcare Epidemiology of timicrobial use for hospitalized adults. Many of these
America.
studies have focused on adults in intensive care units.
Reprints or correspondence: Dr. Thomas M. Hooton, University of Miami Miller
School of Medicine, Highland Professional Bldg., 1801 NW 9th Ave., Ste. 420 (M- Only a handful of studies have focused on hospitalized
716), Miami, FL 33136 ([email protected]). newborns, children, and adolescents. Few studies have
Clinical Infectious Diseases 2007; 44:159–77
2006 by the Infectious Diseases Society of America. All rights reserved.
included substantial populations of severely immuno-
1058-4838/2007/4402-0001$15.00 compromised patients, such as patients undergoing
Antimicrobial Stewardship Guidelines • CID 2007:44 (15 January) • 159

hematopoetic stem cell transplantation or receiving chemo- clinical pharmacist with infectious diseases training (A-II) who
therapy likely to cause prolonged neutropenia. Nonetheless, the should be compensated for their time (A-III), with the inclusion
recommendations in these guidelines are likely to be broadly of a clinical microbiologist, an information system specialist,
applicable to all hospitalized patients. an infection control professional, and hospital epidemiologist
The ratings of the practices recommended in this document being optimal (A-III). Because antimicrobial stewardship, an
reflect the likely impact of stewardship practices on improving important component of patient safety, is considered to be a
antimicrobial use and, consequently, minimizing the emergence medical staff function, the program is usually directed by an
and spread of antimicrobial resistance. Each recommendation infectious diseases physician or codirected by an infectious dis-
is rated on the basis of the strength of the recommendation eases physician and a clinical pharmacist with infectious dis-
and the quality of evidence supporting it, using the rating sys- eases training (A-III).
tem of the Infectious Disease Society of America (IDSA), as 2. Collaboration between the antimicrobial stewardship
shown in table 1 [1]. The ratings provided also reflect the likely team and the hospital infection control and pharmacy and
ability of the recommendation to reduce health care costs. Some therapeutics committees or their equivalents is essential (A-III).
strategies to reduce resistance may actually result in an increase 3. The support and collaboration of hospital administra-
in drug acquisition costs as part of a more comprehensive plan tion, medical staff leadership, and local providers in the de-
to reduce overall costs, including the attributable costs of re- velopment and maintenance of antimicrobial stewardship pro-

sistance. In situations in which the likely impact of a recom- grams is essential (A-III). It is desirable that antimicrobial
mendation on appropriate use of antimicrobials and health care stewardship programs function under the auspices of quality
costs diverge or in which cost data are not available, separate assurance and patient safety (A-III).
ratings are given. 4. The infectious diseases physician and the head of phar-
Effective antimicrobial stewardship programs can be finan- macy, as appropriate, should negotiate with hospital admin-
cially self-supporting and improve patient care [2–7] (A-II). istration to obtain adequate authority, compensation, and ex-
Comprehensive programs have consistently demonstrated a de- pected outcomes for the program (A-III).
crease in antimicrobial use (22%–36%), with annual savings of 5. Hospital administrative support for the necessary in-
$200,000–$900,000 in both larger academic hospitals [2, 3, 5, frastructure to measure antimicrobial use and to track use on
7, 8] and smaller community hospitals [4, 6]. Thus, health care an ongoing basis is essential (A-III).
facilities are encouraged to implement antimicrobial steward- 6. There are 2 core strategies, both proactive, that provide
ship programs. A comprehensive evidence-based stewardship the foundation for an antimicrobial stewardship program.
program to combat antimicrobial resistance includes elements These strategies are not mutually exclusive.
chosen from among the following recommendations based on A. Prospective audit with intervention and feedback.
local antimicrobial use and resistance problems and on available Prospective audit of antimicrobial use with direct interaction
resources that may differ, depending on the size of the insti- and feedback to the prescriber, performed by either an infec-
tution or clinical setting. tious diseases physician or a clinical pharmacist with infectious
1. Core members of a multidisciplinary antimicrobial ste- diseases training, can result in reduced inappropriate use of
wardship team include an infectious diseases physician and a antimicrobials (A-I).
Table 1. Infectious Diseases Society of America–United States Public Health Service grading
system for ranking recommendations in clinical guidelines.
Category, grade Definition

Strength of recommendation
A Good evidence to support a recommendation for use
B Moderate evidence to support a recommendation for use
C Poor evidence to support a recommendation for use
Quality of evidence
I Evidence from ⭓1 properly randomized, controlled trial
II Evidence from ⭓1 well-designed clinical trial, without randomization;
from cohort or case-controlled analytic studies (preferably from 11
center); from multiple time-series; or from dramatic results from
uncontrolled experiments
III Evidence from opinions of respected authorities, based on clinical
experience, descriptive studies, or reports of expert committees
NOTE. Adapted from [1].
160 • CID 2007:44 (15 January) • Dellit et al.

B. Formulary restriction and preauthorization. For- with multidrug-resistant pathogens, to increase the breadth of
mulary restriction and preauthorization requirements can lead coverage and the likelihood of adequate initial therapy (A-II).
to immediate and significant reductions in antimicrobial use F. Streamlining or de-escalation of therapy. Stream-
and cost (A-II) and may be beneficial as part of a multifaceted lining or de-escalation of empirical antimicrobial therapy on
response to a nosocomial outbreak of infection (B-II). The use the basis of culture results and elimination of redundant com-
of preauthorization requirements as a means of controlling bination therapy can more effectively target the causative path-
antimicrobial resistance is less clear, because a long-term ben- ogen, resulting in decreased antimicrobial exposure and sub-
eficial impact on resistance has not been established, and in stantial cost savings (A-II).
some circumstances, use may simply shift to an alternative G. Dose optimization. Optimization of antimicrobial
agent with resulting increased resistance (B-II). In institutions dosing based on individual patient characteristics, causative or-
that use preauthorization to limit the use of selected antimi- ganism, site of infection, and pharmacokinetic and pharma-
crobials, monitoring overall trends in antimicrobial use is nec- codynamic characteristics of the drug is an important part of
essary to assess and respond to such shifts in use (B-III). antimicrobial stewardship (A-II).
H. Parenteral to oral conversion. A systematic plan
7. The following elements may be considered and pri-
for parenteral to oral conversion of antimicrobials with excel-
oritized as supplements to the core active antimicrobial ste-
lent bioavailability, when the patient’s condition allows, can

wardship strategies based on local practice patterns and re-
decrease the length of hospital stay and health care costs (A-
sources.
I). Development of clinical criteria and guidelines allowing
A. Education. Education is considered to be an es-
switch to use of oral agents can facilitate implementation at
sential element of any program designed to influence prescrib-
the institutional level (A-III).
ing behavior and can provide a foundation of knowledge that 8. Health care information technology in the form of elec-
will enhance and increase the acceptance of stewardship strat- tronic medical records (A-III), computer physician order entry
egies (A-III). However, education alone, without incorporation (B-II), and clinical decision support (B-II) can improve anti-
of active intervention, is only marginally effective in changing microbial decisions through the incorporation of data on pa-
antimicrobial prescribing practices and has not demonstrated tient-specific microbiology cultures and susceptibilities, hepatic
a sustained impact (B-II). and renal function, drug-drug interactions, allergies, and cost.
B. Guidelines and clinical pathways. Multidisci- However, implementation of these features has been slow, and
plinary development of evidence-based practice guidelines conformation of the technology to the clinical environment
incorporating local microbiology and resistance patterns can remains a challenge.
improve antimicrobial utilization (A-I). Guideline implemen- 9. Computer-based surveillance can facilitate good ste-
tation can be facilitated through provider education and feed- wardship by more efficient targeting of antimicrobial interven-
back on antimicrobial use and patient outcomes (A-III). tions, tracking of antimicrobial resistance patterns, and iden-
C. Antimicrobial cycling. There are insufficient data tification of nosocomial infections and adverse drug events
to recommend the routine use of antimicrobial cycling as a (B-II).
means of preventing or reducing antimicrobial resistance over 10. The clinical microbiology laboratory plays a critical
a prolonged period of time (C-II). Substituting one antimi- role in antimicrobial stewardship by providing patient-specific
crobial for another may transiently decrease selection pressure culture and susceptibility data to optimize individual antimi-
and reduce resistance to the restricted agent. Unless the resis- crobial management and by assisting infection control efforts
tance determinant has been eliminated from the bacterial pop- in the surveillance of resistant organisms and in the molecular
ulation, however, reintroduction of the original antimicrobial epidemiologic investigation of outbreaks (A-III).
is again likely to select for the expression of the resistance 11. Both process measures (did the intervention result in
determinant in the exposed bacterial population. the desired change in antimicrobial use?) and outcome mea-
sures (did the process implemented reduce or prevent resistance
D. Antimicrobial order forms. Antimicrobial order
or other unintended consequences of antimicrobial use?) are
forms can be an effective component of antimicrobial ste-
useful in determining the impact of antimicrobial stewardship
wardship (B-II) and can facilitate implementation of practice
on antimicrobial use and resistance patterns (B-III).
guidelines.
E. Combination therapy. There are insufficient data
INTRODUCTION
to recommend the routine use of combination therapy to pre-
vent the emergence of resistance (C-II). Combination therapy Purpose. In recognition that antimicrobial resistance results
does have a role in certain clinical contexts, including use for in increased morbidity, mortality, and cost of health care, the
empirical therapy for critically ill patients at risk of infection IDSA initially published guidelines for improving the use of

antimicrobial agents in hospitals in 1988 [9] and then jointly Table 2. Causal associations between antimicrobial use and
published guidelines with the Society for Healthcare Epide- the emergence of antimicrobial resistance.
miology of America in 1997 for the prevention of antimicrobial
Changes in antimicrobial use are paralleled by changes in the
resistance in hospitals [10]. However, subsequent surveys of prevalence of resistance.
hospitals have found that practices to improve antimicrobial Antimicrobial resistance is more prevalent in health
use are frequently inadequate and not routinely implemented care–associated bacterial infections, compared with those from
[11–13]. The purpose of these guidelines is to build on the community-acquired infections.
previous position statements, as well as to provide evidence- Patients with health care–associated infections caused by resis-
tant strains are more likely than control patients to have re-
based recommendations for developing a program to enhance ceived prior antimicrobials.
antimicrobial stewardship in the hospital setting to improve Areas within hospitals that have the highest rates of antimicrobial
the quality of care. These guidelines are not a substitute for resistance also have the highest rates of antimicrobial use.
clinical judgment, and clinical discretion is required in the ap- Increasing duration of patient exposure to antimicrobials increases
the likelihood of colonization with resistant organisms.
plication of guidelines to individual patients.
Effective antimicrobial stewardship programs, also known as NOTE. A causal association between antimicrobial use and the emergence
of antimicrobial resistance has been reviewed elsewhere [9, 19–22] and is
antimicrobial management programs, can be financially self- strongly suggested on the basis of several lines of evidence that are derived
supporting and can improve patient care [2–7] (A-II). Anti- from patient and population levels of analysis, colonization and infection data,

and retrospective and prospective studies [23–31]. Adapted from [10].
microbial stewardship includes not only limiting inappropriate
use but also optimizing antimicrobial selection, dosing, route,
and duration of therapy to maximize clinical cure or prevention
coccus bloodstream infections [40]. Similar adverse outcomes
of infection while limiting the unintended consequences, such
have also been reported for infections with resistant gram-
as the emergence of resistance, adverse drug events, and cost. negative organisms, including Pseudomonas, Acinetobacter, and
Given the emergence of multidrug-resistant pathogens and Enterobacter species and extended-spectrum b-lactamase–
their impact on clinical care, appropriate use of antimicrobial producing organisms [41]. A case-control study found that
agents has become a focus of patient safety and quality assur- third-generation cephalosporin–resistant Enterobacter infec-
ance along with medication errors, allergy identification, and tions were associated with increased mortality (relative risk,
drug-drug interactions [14]. The ultimate goal of antimicrobial 5.02), length of hospital stay (1.5-fold increase), and an attrib-
stewardship is to improve patient care and health care utable cost of $29,379 [42]. The emergence of infections with
outcomes. multidrug-resistant gram-negative organisms, combined with
From the institutional perspective, antimicrobials account a paucity of new drug development, has unfortunately led to
for upwards of 30% of hospital pharmacy budgets [15]. It has the resurgent use of colistin, a polymyxin antimicrobial pre-
been recognized for several decades that up to 50% of anti- viously abandoned because of its high rates of nephrotoxicity
microbial use is inappropriate, adding considerable cost to pa- and neurotoxicity [43]. In 1998, the Institute of Medicine es-
tient care [8, 9, 15–18]. In addition to direct pharmacy ac- timated that the annual cost of infections caused by antimi-
quisition costs, numerous reports suggest that inappropriate crobial-resistant bacteria was $4–$5 billion [44].
and unnecessary antimicrobial use leads to increased selection Methods. The recommendations in this guideline are based
of resistant pathogens (table 2). Once antimicrobial resistance on a review of published studies identified through a search of
emerges, it can have a significant impact on patient morbidity the PubMed database (search terms used alone and in com-
and mortality, as well as increased health care costs [32, 33]. bination included “antimicrobial,” “antibiotic,” “stewardship,”
Bacteremia [34, 35] and surgical site infections [36] due to “management,” “resistance,” “cost,” “education,” “guidelines,”
methicillin-resistant Staphylococcus aureus (MRSA) have been “restriction,” “cycling,” “order forms,” and “combination ther-
associated with a higher mortality rate than similar infections apy”) supplemented by review of references of relevant articles
due to methicillin-susceptible S. aureus, with the mean attrib- to identify additional reports. Committee members were also
utable cost of an MRSA infection ranging from $9275 to asked to cite additional relevant studies to support the rec-
$13,901 [36, 37]. Similarly, compared with vancomycin-sus- ommendations. Because of the limited number of randomized,
ceptible Enterococcus faecium infections, bloodstream infections controlled trials, results from prospective cohort studies, case-
due to vancomycin-resistant E. faecium (VRE) were associated control studies, longitudinal time series, and other descriptive
with decreased survival (24% vs. 59%), increased length of studies are included in the review. The ratings of the practices
hospital stay (34.8 vs. 16.7 days), and an attributable cost of recommended in this document reflect the likely impact of such
$27,190 per episode [38, 39]. A meta-analysis of 9 studies of practices on improving antimicrobial use and, ultimately, an-
VRE bloodstream infections found an attributable excess mor- timicrobial resistance. Given the association between antimi-
tality of 30%, compared with vancomycin-susceptible Entero- crobial use and the selection of resistant pathogens, rates of

inappropriate antimicrobial use are considered as surrogate program (A-III). It is essential that there be hospital admin-
markers for the avoidable impact on antimicrobial resistance. istrative support for the necessary infrastructure, to measure
The strength of the recommendations and quality of evidence antimicrobial use and to track use on an ongoing basis (A-III).
are rated using IDSA criteria (table 1) [1]. Individual studies It is desirable that antimicrobial stewardship programs function
were evaluated both for their impact on the targeted antimi- under the auspices of quality assurance and patient safety. Prior
crobial(s) or resistance problem and for any secondary impact to program implementation, the antimicrobial stewardship
on local antimicrobial use and resistance patterns. The ratings strategic plan should be presented to and approved by the chiefs
also reflect the likely ability of the recommendation to reduce of professional services, hospital medical staff executive com-
health care costs. In situations in which the likely impact of a mittee, and/or other medical staff governing bodies, to ensure
recommendation on appropriate use of antimicrobials and their acceptance and support.
health care costs diverge or cost data are not available, separate
ratings are given. Recommendations reflect a compilation of Recommendations
the studies in each section, as well as the opinions of the com- • Core members of a multidisciplinary antimicrobial ste-
mittee members. wardship team include an infectious diseases physician and
a clinical pharmacist with infectious diseases training (A-
GUIDELINES FOR DEVELOPING AN II) who should be compensated for their time (A-III), with

INSTITUTIONAL PROGRAM TO ENHANCE the inclusion of a clinical microbiologist, an information
ANTIMICROBIAL STEWARDSHIP system specialist, an infection control professional, and hos-
pital epidemiologist being optimal (A-III). Because anti-
microbial stewardship, an important component of patient
THE ANTIMICROBIAL STEWARDSHIP TEAM
safety, is considered to be a medical staff function, the pro-
AND ADMINISTRATIVE SUPPORT
gram is usually directed by an infectious diseases physician
It is essential that the antimicrobial stewardship team includes or codirected by an infectious diseases physician and a clin-
an infectious diseases physician and a clinical pharmacist with ical pharmacist with infectious diseases training (A-III).
infectious diseases training and that both of these individuals • Collaboration between the antimicrobial stewardship team
are compensated appropriately for their time. Optimally, the and the hospital infection control and pharmacy and ther-
team should include a clinical microbiologist who can provide apeutics committees, or their equivalents, is essential (A-
surveillance data on antimicrobial resistance, as well as an in- III).
formation system specialist who can provide the computer sup- • The support and collaboration of hospital administration,
port necessary for surveillance and implementation of rec- medical staff leadership, and local providers in the devel-
ommendations. In addition, it is optimal that the team includes opment and maintenance of antimicrobial stewardship pro-
an infection control professional and hospital epidemiologist grams is essential (A-III). It is desirable that antimicrobial
to coordinate efforts on improving antimicrobial use, because stewardship programs function under the auspices of quality
reduction of antimicrobial resistance is a common goal of these assurance and patient safety (A-III).
persons. Because antimicrobial stewardship, an important com- • The infectious diseases physician and the head of pharmacy,
ponent of patient safety, is considered to be a medical staff as appropriate, should negotiate with hospital administra-
function, the program is usually directed by an infectious dis- tion to obtain adequate authority, compensation, and ex-
eases physician or codirected by an infectious diseases physician pected outcomes for the program (A-III).
and a clinical pharmacist with infectious diseases training. The • Hospital administrative support for the necessary infrastruc-
clinical pharmacist should be knowledgeable on the appropriate ture to measure antimicrobial use and to track use on an
use of antimicrobials, and appropriate training should be made ongoing basis is essential (A-III).
available to achieve and maintain this expertise. It is essential
that there be support and collaboration between the antimi-
ELEMENTS OF AN ANTIMICROBIAL
crobial stewardship team and the hospital infection control and
STEWARDSHIP PROGRAM
pharmacy and therapeutics committees or their equivalents.
The support and collaboration of hospital administration, The best strategies for the prevention and containment of an-
medical staff leadership, and local providers in the development timicrobial resistance are not definitively established, because
and maintenance of antimicrobial stewardship programs is es- there is a paucity of randomized, controlled trials in this field
sential to success of the program. In this regard, the infectious [45]. Often, multiple interventions have been made simulta-
diseases physician and the head of pharmacy, as appropriate, neously, making it difficult to assess the benefit attributable to
should negotiate with hospital administration to obtain ade- any one specific intervention. However, a comprehensive pro-
quate authority, compensation, and expected outcomes for the gram that includes active monitoring of resistance, fostering of

appropriate antimicrobial use, and collaboration with an ef- still have a significant impact, as illustrated by a small, 120-
fective infection control program to minimize secondary spread bed community hospital that used an infectious diseases phy-
of resistance [46, 47] is considered to be optimal [48]. A com- sician and clinical pharmacist 3 days per week to review patients
prehensive evidence-based stewardship program to combat an- receiving multiple, prolonged, or high-cost courses of anti-
timicrobial resistance includes elements chosen from among microbial therapy [4]. Sixty-nine percent of 488 recommen-
the following strategies, which are based on local antimicrobial dations were implemented, resulting in a 19% reduction in
use and resistance problems, and on available resources that antimicrobial expenditures for an estimated annual savings of
may differ depending on the size of the institution or clinical $177,000, compared with the preintervention period. In these
setting. studies, interventions were communicated to prescribers either
verbally or in writing. Written communication was typically
Active Antimicrobial Stewardship Strategies accomplished by using special, nonpermanent forms that were
Prospective audit with intervention and feedback. Pro- placed in the medical record or chart but were subsequently
spective audit of antimicrobial use with intervention and feed- removed after the intervention or at the time of discharge from
back to the prescriber have been demonstrated to improve the hospital. Each intervention provides the opportunity for
antimicrobial use. In a large teaching hospital, house staff were provider education.
Effective audit with intervention and feedback can be facil-

randomized by the medical service to receive either no inter-
vention or one-on-one education by a clinical specialist (aca- itated through computer surveillance of antimicrobial use, al-
demic detailing) on a patient-specific basis, emphasizing mi- lowing the targeting of specific services or units where problems
exist, as well as identification of patients receiving particular
crobiologic data, local resistance patterns, and clinical literature,
agents or combinations of agents that might benefit from
when the pharmacy received an order for either levofloxacin
intervention.
or ceftazidime. This resulted in a 37% reduction in the number
of days of unnecessary levofloxacin or ceftazidime use by de-
Recommendation
creasing the duration of therapy, as well as reducing new starts,
suggesting that house staff learned not to initiate unnecessary
• Prospective audit of antimicrobial use with direct interac-
tion and feedback to the prescriber, performed by either an
antibiotic treatment regimens [49]. At a 600-bed tertiary teach-
infectious diseases physician or a clinical pharmacist with
ing hospital, inpatients receiving parenteral antimicrobials cho-
infectious diseases training, can result in reduced inappro-
sen by their primary care physician were randomized to an
priate use of antimicrobials (A-I).
intervention group that received antimicrobial-related sugges-
tions from an infectious diseases fellow and a clinical phar- Formulary restriction and preauthorization requirements
macist versus no antimicrobial suggestions. Physicians in the for specific agents. Most hospitals have a pharmacy and ther-
intervention group received 74 suggestions for 62 of 127 pa- apeutics committee or an equivalent group that evaluates drugs
tients, including suggestions on a more appropriate agent, route for inclusion on the hospital formulary on the basis of con-
of administration, dosing, discontinuation of the drug, or tox- siderations of therapeutic efficacy, toxicity, and cost while lim-
icity monitoring. Eighty-five percent of the suggestions were iting redundant new agents with no significant additional ben-
implemented, resulting in 1.6 fewer days of parenteral therapy efit. Antimicrobial restriction—either through formulary
and a cost savings of $400 per patient, with no adverse impact limitation by this method or by the requirement of preau-
on clinical response, compared with the control group [50]. thorization and justification—is the most effective method of
There was a trend, however, toward increasing rates of read- achieving the process goal of controlling antimicrobial use.
mission in the intervention group, emphasizing the need to Longitudinal studies implementing restrictive policies have
monitor the impact of such interventions designed to decrease demonstrated significant initial decreases in the use of the tar-
length of hospital stay. geted antimicrobials, with annual antimicrobial cost savings
Prospective audit and interventions by a clinical pharmacist ranging upwards of $800,000 [14, 51–57]. The achievement of
and infectious diseases physician at a medium-sized community the outcome goal of reducing antimicrobial resistance has not
hospital resulted in a 22% decrease in the use of parenteral been as clear, as illustrated by the following studies.
broad-spectrum antimicrobials, despite a 15% increase in pa- Both formulary restriction [58] and preauthorization re-
tient acuity over a 7-year period [3]. They also demonstrated quirements for use of clindamycin [59] during nosocomial ep-
a decrease in rates of C. difficile infection and nosocomial in- idemics of C. difficile infection have led to prompt cessation of
fection caused by drug-resistant Enterobacteriaceae, compared the outbreaks, whereas preapproval restriction of broad-
with the preintervention period. spectrum antimicrobials has led to short-term increased sus-
In hospitals where daily review of antimicrobial use is not ceptibilities among gram-negative pathogens, such as Pseudo-
feasible because of limited resources, a scaled-down model can monas aeruginosa, Klebsiella pneumoniae, and Enterobacter

cloacae, during a 6–12-month period [57, 60]. Restriction of rin-resistant Klebsiella, a preapproval policy was implemented
vancomycin and third-generation cephalosporins in response for cephalosporins. This resulted in an 80% reduction in hos-
to increasing rates of VRE has demonstrated mixed results [61– pital-wide cephalosporin use and a subsequent 44% reduction
63]. Fecal VRE colonization rates of 47% (despite barrier pre- in the incidence of ceftazidime-resistant Klebsiella throughout
cautions) led one center to restrict vancomycin and cefotaxime the medical center, as well as a 71% reduction in the ICUs.
use while encouraging the replacement of third-generation Concomitantly, however, imipenem use increased 141%, ac-
cephalosporins with b-lactam/b-lactamase inhibitor combina- companied by a 69% increase in the incidence of imipenem-
tions. This led to a reduction in the rates of monthly use of resistant P. aeruginosa. This untoward restrictive effect of
vancomycin, cefotaxime, and ceftazidime by 34%, 84%, and “squeezing the balloon” may counteract the originally sought
55%, respectively, and rates of ampicillin-sulbactam and benefits [69]. Furthermore, restricting use of a single drug to
piperacillin-tazobactam use increased. This was accompanied prevent or reverse antimicrobial resistance may be ineffective,
by a decrease in the fecal VRE point prevalence from 47% to because multiple antimicrobials may be associated with changes
15% during 6 months [59]. In contrast, in another study, the in susceptibility to other drugs for a given pathogen [70].
prevalence of VRE increased from 17% to 30%, despite the
Recommendation
restriction on the use of vancomycin and third-generation
cephalosporins during a 10-year period [64]. The interpretation • Formulary restriction and preauthorization requirements

can lead to immediate and significant reductions in anti-
of these study results is often confounded by concomitant
microbial use and cost (A-II) and may be beneficial as part
changes in infection control practices and by the influence of
of a multifaceted response to a nosocomial outbreak of
nonrestricted antimicrobial agents on gut flora.
infection (B-II). The use of preauthorization requirements
Studies of antibiotic-restriction policies among pediatric pa-
as a means of controlling antimicrobial resistance is less
tients have demonstrated inconsistent results. A crossover study
clear, because a long-term beneficial impact on resistance
of 2 neonatal intensive care units (ICUs) compared 2 ap-
has not been established, and in some circumstances, use
proaches for empirical treatment of early- and late-onset sus-
may simply shift to an alternative agent with resulting in-
pected sepsis—a “broad-spectrum” regimen consisting of am-
creased resistance (B-II). In institutions that use preau-
picillin and cefotaxime versus a “narrow-spectrum” regimen
thorization to limit the use of selected antimicrobials, mon-
consisting of penicillin and tobramycin—on the prevalence of
itoring overall trends in antimicrobial use is necessary to
colonization with bacteria resistant to each of the regimens [65].
assess and respond to such shifts in use (B-III).
The narrow-spectrum regimen was associated with a markedly
lower prevalence of colonization with resistant gram-negative
bacilli. In contrast, a quasi experimental study from a pediatric Supplemental Antimicrobial Stewardship Strategies
ICU of a policy to restrict ceftazidime use (piperacillin- Education. Education is the most frequently employed in-
tazobactam was the preferred regimen) found no change in the tervention and is considered to be an essential element of any
incidence of colonization with ceftazidime-resistant gram- program designed to influence prescribing behavior. Educa-
negative bacilli, although there was a decrease in the prevalence tional efforts include passive activities, such as conference pre-
of colonization with specific species of gram-negative bacilli sentations, student and house staff teaching sessions, and pro-
that commonly harbor inducible AmpC b-lactamases (e.g., E. vision of written guidelines or e-mail alerts. However, education
cloacae, Serratia marcesens, Citrobacter freundii, and P. aerugi- alone, without incorporation of active intervention, is only
nosa) [66]. marginally effective and has not demonstrated a sustained im-
The effectiveness of a preauthorization program depends on pact [71–73].
who is making the recommendations. Restriction of cefotaxime Step-wise implementation of an antimicrobial stewardship
use through a program requiring approval from a chief resident program initially with passive strategies, such as education and
or attending physician had no impact on its use [67]. Rec- order forms, followed by an active strategy with prospective audit
ommendations from an antimicrobial management team con- and intervention demonstrated progressive decreases in anti-
sisting of a pharmacist and an infectious diseases physician microbial consumption, resulting in a savings of $913,236 over
resulted in increased antimicrobial appropriateness, increased 18 months. During the period of active intervention, 25% of
clinical cure, and a trend towards improved economic outcome, antimicrobial orders were modified (86% resulted in less expen-
compared with recommendations made by infectious diseases sive therapy, and 47% resulted in use of a drug with a narrower
fellows [68]. spectrum of activity), resulting in a significant increase in mi-
The challenge of antimicrobial restriction and its effect on crobiologically based prescribing (63% vs. 27%) [71].
antimicrobial resistance is exemplified in a study by Rahal et In an attempt to improve adherence to recommendations
al. [27]. In response to an increasing incidence of cephalospo- for perioperative antimicrobial prophylaxis, a before-and-after

study compared prescribing practices after distribution of an suggest that improving antimicrobial use through the use of
educational handbook with those after the introduction of an guidelines may decrease the emergence of resistant pathogens.
order form. The educational handbook led to a marginal im- The increasing incidence of multidrug-resistant organisms
provement in compliance (from 11% to 18%), whereas intro- in cases of HAP and VAP, the diagnostic challenge of these
duction of the order form led to significantly improved com- entities, and the mortality benefit associated with initial ap-
pliance (from 17% to 78%) [73]. propriate therapy [77] have led to an increased use of broad-
spectrum antimicrobials, which must be balanced against fur-
Recommendation ther selection of resistant pathogens. Invasive diagnosis of VAP
with quantitative bronchoscopy for diagnosis and antimicrobial
• Education is considered to be an essential element of any
program designed to influence prescribing behavior and can guidance led to reduced mortality at 14 days and a decrease in
provide a foundation of knowledge that will enhance and antimicrobial use [78]. Another strategy to address the inap-
increase the acceptance of stewardship strategies (A-III). propriate use of antimicrobials in the ICU setting used an al-
However, education alone, without incorporation of active gorithm incorporating the clinical pulmonary infection score
intervention, is only marginally effective in changing anti- to identify patients with a low likelihood of pneumonia. Pa-
microbial prescribing practices and has not demonstrated a tients randomized to the intervention group who continued to
have a low clinical pulmonary infection score (⭐6) had their

sustained impact (B-II).
antimicrobial therapy discontinued at day 3, and the control
group received the standard 10–21 days of therapy. This led to
Guidelines and clinical pathways. Clinical practice guide-
a significant decrease in duration of therapy (3 vs. 9.8 days)
lines are being produced with increasing frequency, with the
and antimicrobial cost ($400 per patient), with no difference
goal of ensuring high-quality care. However, the impact on
in mortality. In addition, the development of antimicrobial
provider behavior and improved clinical outcomes has been
resistance and/or superinfections was less common in the group
difficult to measure. Although physicians usually agree, in prin-
receiving the short-course antimicrobial therapy (15% vs. 35%)
ciple, with national guidelines, the absence of accompanying
[79]. A prospective before-and-after study of a clinical guideline
strategies for local implementation often presents a formidable
for the management of VAP incorporated broad empirical ther-
barrier [74]. Antimicrobial stewardship programs can facilitate
apy based on local microbiology with culture-driven de-esca-
multidisciplinary development of evidence-based practice
lation and a standard 7-day course of therapy. Implementation
guidelines that incorporate local microbiology and resistance
patterns. of the protocol led to increased initial administration of ade-
Randomized implementation of a clinical pathway, com- quate antimicrobial therapy (94% vs. 48%), decreased duration
pared with conventional management of community-acquired of therapy (8.6 vs. 14.8 days), and decreased VAP recurrence
pneumonia, among 20 hospitals led to a 1.7-day decrease in (8% vs. 24%), without affecting patient mortality [80]. The
the median length of hospital stay, an 18% decrease in the rate efficacy of short-course therapy for VAP was subsequently con-
of admissions of low-risk patients, and 1.7 fewer mean days of firmed in a randomized study of 8 versus 15 days of antimi-
intravenous therapy in the intervention group, without an in- crobial therapy in patients with VAP documented by quanti-
crease in complications, readmissions, or mortality [75]. In tative culture of samples obtained by bronchoscopy. There was
another study, multidisciplinary development of practice guide- no difference in mortality or recurrent infection in patients
lines based on evidence in the literature and local microbiology who received the shorter course of therapy, but the short-course
and resistance patterns and implementation in a surgical ICU group did have more antimicrobial-free days (13.1 vs. 8.7) and
led to a 77% reduction in antimicrobial use and cost, a 30% a decreased rate of emergence of multidrug-resistant pathogens
reduction in overall cost of care, decreased mortality among among those patients with recurrences of pulmonary infection
patients with infection, and a trend towards reduced length of (42% vs. 62%) [81]. These studies support the development
ICU stay, compared with the preimplementation time period and implementation of evidence-based guidelines for diagnosis
[76]. Importantly, both of these studies demonstrate that an- and antimicrobial therapy for HAP and VAP.
timicrobial selection is only 1 component in improving the A quasi experimental study in a pediatric hospital in Australia
management of infectious diseases and cannot be done without demonstrated similar results regarding the use of guidelines to
recommendations for diagnosis and testing, admission criteria, improve therapy for common infections [82]. The investigators
nursing care, conversion to oral medication, and discharge provided recommendations for the treatment of childhood in-
planning. Whether the use of guidelines will lead to a long- fections on a laminated card that could be clipped to a hospital
term impact on antimicrobial resistance remains to be deter- badge. When the 6-month period during implementation of
mined, but the following studies of hospital-acquired pneu- the intervention (intervention period) was compared with the
monia (HAP) and ventilator-associated pneumonia (VAP) prior 6 months (baseline period), the intervention was asso-

ciated with substantial increases in the percentage of prescrip- cardiothoracic ICU led to a decreased incidence of VAP due
tions with the correct choice and dose of antimicrobial agents to multidrug-resistant, gram-negative bacteria (1% vs. 4%)
for 2 of 3 indicator infections (pneumonia and orbital/perior- [94]. Restriction of ceftazidime and ciprofloxacin in a medical
bital cellulitis). The cost of third-generation cephalosporins was ICU, combined with cycling of the preferred b-lactam agent at
reduced by more than one-half in the intervention period. monthly intervals, led to a decreased incidence of VAP and
improved susceptibilities for P. aeruginosa. Because these ma-
Recommendation neuvers, as well as de-escalation of therapy based on culture
• Multidisciplinary development of evidence-based practice results, led to a 50% reduction in overall antimicrobial use, the
guidelines incorporating local microbiology and resistance benefit of cycling alone cannot be ascertained [95]. Quarterly
patterns can improve antimicrobial utilization (A-I). Guide- rotation of empirical antimicrobial regimens in a surgical ICU
line implementation can be facilitated through provider ed- for pneumonia and peritonitis/sepsis led to a decreased inci-
ucation and feedback on antimicrobial use and patient out- dence of resistant bacterial infections and mortality due to in-
comes (A-III). fection [96]. However, significant patient population differ-
ences and the simultaneous changes in infection control,
Antimicrobial cycling and scheduled antimicrobial switch. including institution of an antibiotic surveillance team and the
“Antimicrobial cycling” refers to the scheduled removal and introduction of alcohol gel dispensers, confounded interpre-

substitution of a specific antimicrobial or antimicrobial class tation of the results. In addition, only 62%–83% of patients
to prevent or reverse the development of antimicrobial resis- received the “on-cycle” antimicrobial intended in the process
tance within an institution or specific unit. In true cycling, change, resulting in antimicrobial mixing as opposed to time
there is a return to the original antimicrobial after a defined period–based cycling.
time, as opposed to a simple switch of antimicrobials [83–86]. It should be noted that mathematical modeling suggests that
In many respects, cycling is an attempt at controlled hetero- true cycling is unlikely to reduce the evolution or spread of
geneity of antimicrobial use to minimize antimicrobial selection antimicrobial resistance. Rather, such modeling suggests that
pressures. Studies of true antimicrobial cycling are limited and the simultaneous mixed use of different antimicrobial classes
vary in terms of antimicrobial class selection, duration of cy- in a heterogeneous fashion may slow the spread of resistance
cling, therapeutic options offered during cycling periods, and [97, 98].
cycling by time period versus by patient. Concerns about al- In an attempt to examine this hypothesis, a prospective cross-
lergies, adverse drug events, and conflicts with national guide- over study compared the effects of monthly cycling of antip-
lines have led to 10%–50% of patients in cycling programs to seudomonal agents (cefepime or ceftazidime, ciprofloxacin, im-
receive “off-cycle” antimicrobials, resulting in poor implemen- ipenem or meropenem, or piperacillin-tazobactam) with the
tation of the intended process change, with multiple antimi- use of these agents in the same order by consecutive patients
crobials being used at the same time by different patients [85]. (i.e., mixing) [99]. During mixing, a significantly higher pro-
Driven by both increasing resistance among Enterobacteri- portion of patients acquired a strain of P. aeruginosa that was
aceae and pricing changes, the largest cycling experience has resistant to cefepime (9% vs. 3%; P p .01). As in previous
been reported for changes in aminoglycoside use—particularly, cycling studies, however, adherence to the cycling regimen was
substituting amikacin for gentamicin. Such a switch in ami- problematic, with scheduled antimicrobials never accounting
noglycoside use has been associated with a significant reduction for more than 45% of all antipseudomonal antimicrobials. Ad-
in gentamicin resistance [87–93]; however, rapid reintroduction ditional clinical studies to examine optimal cycling parameters
of gentamicin was accompanied by a rapid return of gentamicin and the role of antimicrobial diversity are needed.
resistance [89, 92]. In one institution with 10 years of expe-
rience, this led to an additional cycle of amikacin followed by
a more gradual return of gentamicin, without an associated Recommendation
increase in resistance once the original gentamicin resistance • There are insufficient data to recommend the routine use
plasmids could no longer be detected [92]. This last example of antimicrobial cycling as a means of preventing or re-
highlights the importance of understanding and monitoring ducing antimicrobial resistance over a prolonged period of
mechanisms of resistance over the long term when developing time (C-II). Substituting one antimicrobial for another may
protocols for antimicrobial cycling. Once antimicrobial resis- transiently decrease selection pressure and reduce resistance
tance emerges, it will often persist even in the absence of direct to the restricted agent. Unless the resistance determinant
antimicrobial selection pressure, potentially minimizing the im- has been eliminated from the bacterial population, however,
pact of antimicrobial removal strategies [21]. reintroduction of the original antimicrobial is again likely
A switch from the empirical use of ceftazidime to cipro- to select for the expression of the resistance determinant in
floxacin for suspected gram-negative bacterial infection in a the exposed bacterial population.

Antimicrobial order forms. Antimicrobial order forms de- load combined with a high frequency of mutational resistance
crease antimicrobial consumption in longitudinal studies during therapy. Classic examples are tuberculosis or HIV in-
through the use of automatic stop orders and the requirement fection. There is often debate about the role of combination
of physician justification [100, 101]. Prior to more recent therapy in serious infections due to gram-negative organisms,
studies further defining the optimal timing and duration of such as Pseudomonas species, but clear evidence supporting a
perioperative antimicrobial prophylaxis [102, 103], use of per- clinical benefit or resistance benefit is lacking [108–118]. A
ioperative prophylactic order forms with automatic discon- meta-analysis of randomized, controlled trials comparing a b-
tinuation at 2 days resulted in a decrease in the mean duration lactam plus an aminoglycoside as combination therapy with b-
of antimicrobial prophylaxis (from 4.9 to 2.4 days) and a lactam monotherapy for the treatment of hospitalized patients
decrease in the percentage of patients receiving perioperative with serious infections found no difference in the emergence
prophylaxis for 12 days (from 85% to 44%) [100]. The rate of antimicrobial resistance. In fact, b-lactam monotherapy was
of inappropriate initiation of antimicrobial prophylaxis post- associated with fewer superinfections [119].
operatively decreased from 30% to 11% with use of the order
Recommendation
form. The use of an order form for all inpatient antimicrobial
orders in an 800-bed hospital that required clinical indication, • There are insufficient data to recommend the routine use
of combination therapy to prevent the emergence of resis-
as well as a defined duration before order renewal, led to a 30%

tance (C-II). Combination therapy does have a role in cer-
decrease in antibiotic courses and a 2% decrease in the hospital
tain clinical contexts, including use for empirical therapy
pharmacy budget for parenteral antibiotics over a 25-month
for critically ill patients at risk of infection with multidrug-
period, during which time most hospitals were experiencing an
resistant pathogens, to increase the breadth of coverage and
increase in expenditures [101]. Use of an antibiotic order form
the likelihood of adequate initial therapy (A-II).
for vancomycin did not improve appropriate use of vancomycin
in a pediatric hospital [104]. Automatic stop orders should not Streamlining or de-escalation of therapy. Good steward-
replace clinical judgment, and renewal requirements must be ship to optimize empirical initial antimicrobial therapy may
clearly communicated to providers to avoid inappropriate treat- conflict with good stewardship to promote judicious use, be-
ment interruptions. cause continuing excessively broad therapy contributes to the
selection of antimicrobial resistant pathogens [120]. This con-
Recommendation flict can be resolved when culture results become available by
• Antimicrobial order forms can be an effective component streamlining or de-escalating antimicrobial therapy to more
of antimicrobial stewardship (B-II) and can facilitate im- targeted therapy that decreases antimicrobial exposure and con-
plementation of practice guidelines. tains cost. De-escalation may also include discontinuation of
empirical antimicrobial therapy based on clinical criteria and
Combination therapy: prevention of resistance versus re-
negative culture results as demonstrated in the management of
dundant antimicrobial coverage. The rationale for combi-
suspected VAP [79, 107, 121]. Review by a pharmacist and an
nation antimicrobial therapy includes broad-spectrum empir-
infectious diseases physician of 625 patients receiving combi-
ical therapy for serious infections, improved clinical outcomes,
nation antimicrobial therapy led to streamlining recommen-
and the prevention of resistance. Inadequate initial antimicro-
dations in 54% of antimicrobial courses over 7 months, re-
bial therapy was found to be an independent risk factor for
sulting in a projected annual savings of $107,637 [122].
mortality in nonurinary infections due to extended-spectrum
In another study, a computer query to mine the hospital
b-lactamase–producing Escherichia coli and Klebsiella species
pharmacy database followed by targeted review by an infectious
[105]. Similarly, inadequate early antimicrobial coverage has
diseases clinical pharmacist facilitated the identification of po-
been associated with increased mortality in patients with micro-
tentially redundant antimicrobial combinations in 16% of pa-
biologically confirmed severe sepsis (39% vs. 24%) [106] and
tients receiving ⭓2 antimicrobials. Even after accepting the
critically ill ICU patients (42% vs. 18%) [55], leading to in-
debatable “double gram-negative coverage,” 71% of the com-
corporation of empirical combination therapy for late-onset
binations were deemed to be inappropriate. Interestingly, half
VAP in the recent IDSA–American Thoracic Society guidelines
of the redundancy was due to physician prescribing error,
[107]. These studies highlight the need to assess risk factors for
whereas the other half was due to medication ordering and
multidrug-resistant pathogens when selecting empirical anti-
distribution system errors. The annualized potential savings
microbial therapy for critically ill patients.
from this intervention was estimated to be $60,000, and ∼3500
However, in many situations, combination therapy is re-
redundant inpatient antibiotic–days were avoided [123].
dundant and unnecessary. Evidence supporting the role of com-
bination antimicrobial therapy for the prevention of resistance Recommendation
is limited to those situations in which there is a high organism • Streamlining or de-escalation of empirical antimicrobial

therapy on the basis of culture results and elimination of enteral to oral therapy decreased length of hospital stay by 1.53
redundant combination therapy can more effectively target days, with cost savings for drug acquisition and reduced length
the causative pathogen, resulting in decreased antimicrobial of hospital stay of $15,149 and $161,072, respectively, over 12
exposure and substantial cost savings (A-II). months [132].
A randomized study of oral linezolid versus intravenous van-
Dose optimization. Optimization of antimicrobial dosing
comycin in patients with complicated skin and soft-tissue in-
that accounts for individual patient characteristics (e.g., age,
fections due to MRSA demonstrated a decreased mean length
renal function, and weight), causative organism and site of
of hospital stay of 5 days for the linezolid group [133], and a
infection (e.g., endocarditis, meningitis, and osteomyelitis), and
switch from vancomycin to oral linezolid for early discharge
pharmacokinetic and pharmacodynamic characteristics of the
from the hospital resulted in an annual savings of $294,750
drug is an important part of antimicrobial stewardship. For
[134]. The use of new agents, such as linezolid, in this manner
instance, the bactericidal activity of b-lactams correlates with
must be done judiciously and with the direct oversight of an
the percentage of time that the drug concentration remains
antimicrobial-management program to balance concerns about
greater than the MIC, whereas fluoroquinolones and aminog-
the development of resistance and added antimicrobial acqui-
lycosides are concentration-dependent agents, with the ratio of
sition costs.
the maximum concentration to the MIC or the ratio of the
A systematic plan for switching from parenteral to oral treat-

area under the curve to the MIC being important predictors
ment may have an added benefit of aiding in early hospital
of activity. Examples of these principles in practice include
discharge planning, if needed, to provide surge capacity during
prolonged or continuous infusion of b-lactams [124], ex-
local or national problems (e.g., epidemic influenza).
tended-interval dosing of aminoglycosides [125], and dosing
of fluoroquinolones for Streptococcus pneumoniae in commu- Recommendation
nity-acquired pneumonia [126, 127] and for Pseudomonas in • A systematic plan for parenteral to oral conversion of an-
HAP and VAP [107]. The use of pharmacokinetic and phar- timicrobials with excellent bioavailability, when the patient’s
macodynamic principles is more likely to be in development condition allows, can decrease length of hospital stay and
of antimicrobial use guidelines than in individual patients’ care. health care costs (A-I). Development of clinical criteria and
Recommendation guidelines allowing conversion to use of oral agents can
facilitate implementation at the institutional level (A-III).
• Optimization of antimicrobial dosing based on individual
patient characteristics, causative organism, site of infection,
and pharmacokinetic and pharmacodynamic characteristics
Computer Surveillance and Decision Support
of the drug is an important part of antimicrobial steward-
Increased focus on medical errors and patient safety led to a
ship (A-II).
series of reports by the Institute of Medicine’s National Round-
Conversion from parenteral to oral therapy. Antimicrobial table on Health Care Quality to emphasize the role of infor-
therapy for patients with serious infections requiring hospital- mation technology in the delivery of health care [135–137].
ization is generally initiated with parenteral therapy. Enhanced The Leapfrog Group has identified computer physician order
oral bioavailability among certain antimicrobials—such as flu- entry (CPOE) as 1 of the 3 most important “leaps” that or-
oroquinolones, oxazolidinones, metronidazole, clindamycin, ganizations can take to substantially improve patient safety.
trimethoprim-sulfamethoxazole, fluconazole, and voricona- CPOE has the potential to incorporate clinical decision support
zole—allows conversion to oral therapy once a patient meets and to facilitate quality monitoring [138]. Progress to this end,
defined clinical criteria. This can result in reduced length of however, remains slow, with only 13% of US hospitals con-
hospital stay, health care costs, and potential complications due verting to electronic medical records and 5% implementing
to intravenous access. CPOE as of 2002 [139, 140].
Randomized studies evaluating early transition from par- The most well-described computer surveillance and decision-
enteral to oral therapy in the management of adults with com- support system related to antimicrobial prescribing linked to
munity-acquired pneumonia have demonstrated significant re- electronic medical records is from LDS Hospital in Salt Lake
ductions in length of hospital stay and cost of care with no City, Utah [141]. This program presents epidemiologic infor-
adverse effect on clinical outcomes [128–130]. A similar de- mation with detailed recommendations and warnings regarding
crease in length of hospital stay, with a 52% reduction in total antimicrobial regimens and courses of therapy. Even if a phy-
health care costs, was noted in the treatment of lower respi- sician overrides the recommendation for the antimicrobial and
ratory tract infections in children, compared with historical selects his or her own treatment plan, the computer still au-
control subjects [131]. A pharmacist-initiated program utilizing tomatically reviews the patient’s allergies and potential drug-
predetermined clinical criteria for general conversion from par- drug interactions, recommending a dosage and interval based

on the patient’s renal and hepatic function. A prospective study investigator has subsequently developed a separate decision-
of the use of this program in an ICU demonstrated significant support system for treatment of bloodstream infection in hos-
reductions in orders for drugs to which the patients had re- pitalized children, although the system has not yet been eval-
ported allergies, excess drug dosages based on renal function, uated prospectively [149].
adverse drug events, antimicrobial-susceptibility mismatches, A randomized study incorporating guidelines for vanco-
antimicrobial costs, and length of hospital stay [142]. Imple- mycin use into a hospital’s CPOE at the time of initial ordering
mentation of a computer-assisted antibiotic-dose monitor and after 72 h of therapy led to 32% fewer vancomycin orders
throughout the same hospital over a 12-month period identified and a 36% reduction in the duration of vancomycin therapy.
1974 (44%) of 4483 patients receiving excessive antimicrobial This resulted in a projected savings of $90,000 [150]. Simply
dosages (based on renal function), leading to more-appropriate adding antimicrobial cost information to antimicrobial sus-
dosing and fewer adverse drug events [143]. Incorporation of ceptibility data resulted in decreased average monthly antimi-
practice guidelines into the system increased the percentage of crobial expenditures by $7636 (17%) in another hospital [151].
surgical patients who received their preoperative prophylactic Despite these initial promising studies, matching the linear
antimicrobials within 2 h of incision from 40% to 99.1% technology of CPOE with complex clinical management that
[144, 145]. can be subjective, interpretive, and reactive has been a challenge
In addition to improving antimicrobial use and care of the at other institutions [152]. Implementation of CPOE at a 750-

individual patient, their system has facilitated the electronic bed teaching hospital to reduce medical errors was actually
surveillance of hospital-acquired infections and adverse drug found to frequently facilitate medication errors [140]. Errors
events. Computer surveillance identified 90% of confirmed included inappropriate dose selection, double-dosing caused by
nosocomial infections, compared with 76% of such infections separate order and discontinuation functions, and gaps in an-
identified by manual surveillance, allowing infection control timicrobial therapy resulting from automatic discontinuation
practitioners to reduce the time required for such activities by orders. In large part, these errors reflected the difficulty of
65% [146]. Automated surveillance of 36,653 patients over 18 implementation rather than the concept of CPOE.
months using defined triggers identified 731 adverse drug The Veterans Administration health care system has been a
events, whereas only 9 were reported through traditional vol- leader in the use of an electronic medical records and CPOE.
untary incident reports [147]. Despite being a model for implementing CPOE, one Veterans
This computer decision-support system was adapted for use Administration hospital found a continuing high rate of adverse
in pediatric patients by Mullett et al. [148], and its effect was drug events in the absence of decision support for drug selec-
tion, dosing, and monitoring [153]. Twenty-six percent of hos-
evaluated in a quasi experimental study. Dosing guidelines were
pital admissions were associated with at least 1 adverse drug
adjusted for pediatric and neonatal populations, to ensure that
event, with medication errors contributing to 27% of these
treatment recommendations were appropriate for infections
adverse events.
common in the pediatric population (e.g., bacterial meningitis),
The lofty goal of merging the electronic records with CPOE
local antimicrobial resistance patterns (e.g., the prevalence of
and clinical decision support to optimize antimicrobial use is
S. pneumoniae with reduced susceptibility to penicillin), special
currently not attainable for most institutions on the basis of
populations (e.g., children with cystic fibrosis), and children
current technology. Depending on available resources, however,
with renal insufficiency. Comparing a 6-month period after
automated targeting of interventions to facilitate antimicrobial
implementation (intervention period) with the prior 6 months
stewardship can be obtained through varying levels of com-
(baseline period), the decision-support system was associated
plexity. Such targeting may include using pharmacy records to
with a 59% decrease in the rate of pharmacy interventions for
identify patients who are receiving broad-spectrum or expensive
erroneous drug doses and 36% and 28% decreases in the rates
antimicrobials, use of simple computer programs that merge
of subtherapeutic and excessive antimicrobial dosing days, re-
hospital pharmacy and microbiology databases, and use of
spectively. There was a 9% decrease in the cost of antimicrobial
more-complex, commercially available software to identify an-
agents during the intervention period. The frequency of adverse
timicrobial interventions.
drug events and antimicrobial-bacterial susceptibility mis-
matches were not significantly different during the intervention Recommendations
period—a finding likely attributable to the low frequency of • Health care information technology in the form of electronic
these events in the baseline period. Clinicians using the system medical records (A-III), CPOE (B-II), and clinical decision
reported that they felt that the program improved their selec- support (B-II) can improve antimicrobial decisions through
tion of antimicrobial agents, increased their awareness of im- the incorporation of data on patient-specific microbiology
pairments in renal function that affected drug dosing, and re- cultures and susceptibilities, hepatic and renal function,
duced the likelihood of adverse drug events. The lead drug-drug interactions, allergies, and cost. However, im-

plementation of these features has been slow, and confor- fections with associated cost savings [161]. If antimicrobial
mation of the technology to the clinical environment re- resistance is due to a clonal outbreak, antimicrobial interven-
mains a challenge. tions may be of limited value, compared with infection control
• Computer-based surveillance can facilitate good steward- interventions. If resistant strains are diverse, antimicrobial in-
ship by more efficient targeting of antimicrobial interven- terventions may be required.
tions, tracking of antimicrobial resistance patterns, and
identification of nosocomial infections and adverse drug Recommendation
events (B-II). • The clinical microbiology laboratory plays a critical role in
antimicrobial stewardship by providing patient-specific cul-
ture and susceptibility data to optimize individual antimi-
Microbiology Laboratory
crobial management and by assisting infection control ef-
The clinical microbiology laboratory plays a critical role in the
forts in the surveillance of resistant organisms and in the
timely identification of microbial pathogens and the perfor-
molecular epidemiologic investigation of outbreaks (A-III).
mance of susceptibility testing [154, 155]. Susceptibility testing
and reporting should be based on the guidelines developed by
the Clinical and Laboratory Standards Institute (CLSI; formerly

the NCCLS) [156]. Prioritization of tested antimicrobials and Monitoring of Process and Outcome Measurements
selective reporting of susceptibility profiles (e.g., not routinely In conjunction with developing local strategies for improving
reporting susceptibility of S. aureus to rifampin to prevent in- antimicrobial stewardship, programs must establish process and
advertent monotherapy with rifampin) can aid in the prudent outcome measures to determine the impact of antimicrobial
use of antimicrobials and direct appropriate therapy based on stewardship on antimicrobial use and resistance patterns. Fur-
local guidelines. The advance of molecular diagnostics allows thermore, health care systems must invest in data systems to
the identification of difficult-to-culture pathogens, potentially allow the evaluation of antimicrobial stewardship as a routine
avoiding the need for extended courses of broad-spectrum em- measure of quality improvement [162]. With antimicrobial ste-
pirical therapy. wardship, the “process goal” is often to change use of a specific
In addition to routine susceptibility testing, the clinical mi- antimicrobial or class of antimicrobials. The related “process
crobiology laboratory should be actively involved in resistance measure” for this goal would determine the degree to which
surveillance. Local antibiograms with pathogen-specific sus- the intervention to change the use of an antimicrobial or class
ceptibility data should be updated at least annually, to optimize of antimicrobials has been successfully implemented, compared
expert-based recommendations for empirical therapy [157]. with baseline levels. The desired “outcome goal” of these pro-
Computerized surveillance can facilitate more-frequent mon- cess changes is to reduce or prevent resistance or other unin-
itoring of antimicrobial resistance trends, as well as provide tended consequences of antimicrobial use. “Outcome mea-
ICU- or ward-specific data and inpatient versus outpatient data, surements” define the degree to which these outcomes are
recognizing that different parts of a health care institution can achieved, such as reduced antimicrobial resistance, adverse drug
have very different patterns of antimicrobial use and resistance events, and cost, as well as unintended consequences, such as
[157]. Besides qualitative determination of antimicrobial resis- rates of C. difficile infection and the use of nontargeted anti-
tance or susceptibility, periodic review of MICs or zone di- microbials as a result of the process change.
ameters in disk-diffusion techniques can detect early trends of Antimicrobial use data based on pharmacy expenditure or
emerging resistance, even within the “susceptibility” cut-offs. dispensing reports often do not account for drug wastage, un-
Kirby-Bauer disk-diffusion methods can also be used to per- used doses returned to pharmacy, or fluctuations in institu-
form the D test for inducible clindamycin resistance for S. tional price structures and discounts [163]. Drug use data can
aureus [158], as well as provide quick screenings for extended- be standardized using the defined daily dose, calculated as the
spectrum b-lactamase– and AmpC b-lactamase–containing or- total number of grams of an antimicrobial agent used divided
ganisms. Finally, the laboratory is an important partner with by the number of grams in an average adult daily dose of the
infection control in the identification and molecular epide- agent [164]. The World Health Organization publishes defined
miologic investigation of local outbreaks of infection. The de- daily dose values for nearly all antimicrobials (http://
velopment of rapid resistance testing will facilitate the surveil- www.whocc.no/atcddd/). The use of defined daily doses is rec-
lance of organisms such as MRSA and VRE, allowing the more ommended so that hospitals may compare their antimicrobial
rapid implementation of infection control measures to prevent use with that of other similar hospitals, recognizing the chal-
secondary spread [159, 160]. Clonal characterization of resis- lenges of interhospital comparisons and the potential need for
tant strains through molecular typing can help focus appro- “risk adjustment.” However, in populations with renal com-
priate interventions, leading to a reduction in nosocomial in- promise (e.g., the elderly population) and for drugs that require

renal dose adjustment, the defined daily dose may be less ac- further studies are needed to determine the optimal processes
curate than measures of antimicrobial-days of therapy [165]. by which the goals of improved clinical outcomes and con-
tainment of antimicrobial resistance can be achieved. However,
Recommendation given the strong association between antimicrobial use and an-
• Both process measures (did the intervention result in the timicrobial resistance (table 2), improving antimicrobial ste-
desired change in antimicrobial use?) and outcome mea- wardship is an important first step.
sures (did the process implemented reduce or prevent re-
sistance or other unintended consequences of antimicrobial RESEARCH PRIORITIES AND FUTURE
use?) are useful in determining the impact of antimicrobial DIRECTIONS
stewardship on antimicrobial use and resistance patterns (B-
III). Because of the limited number of randomized clinical studies
addressing antimicrobial stewardship strategies, many of the
recommendations in this guideline are based on level III evi-
Comprehensive Multidisciplinary Antimicrobial Management dence. Further research and evaluation through appropriately
Programs conducted clinical trials are necessary to determine the best
Through the previous review of individual interventions di- strategies for the prevention and containment of antimicrobial

rected at improving antimicrobial use, it is clear that effective resistance. Recommended topics for investigation are as follows:
antimicrobial stewardship requires a multidisciplinary team ap-
proach that incorporates many of these elements simulta-
neously. The core members of a comprehensive antimicrobial 1. Antimicrobial cycling at the patient, unit, and insti-
management program include an infectious diseases physician tutional level to determine whether cycling is effective and, if
and a clinical pharmacist with infectious diseases training, with so, the optimal antimicrobials to be cycled, the optimal du-
the inclusion of infection control professionals, the hospital ration of the cycles, and the preferred order in which agents
epidemiologist, a clinical microbiologist, and an information should be cycled.
system specialist, when possible [166–174]. The latter is critical 2. Clinical validation of mathematical models suggesting
for linking the patient’s medical record to the pharmacy and that heterogeneous antimicrobial use slows the spread of
microbiology databases, to identify interventions and to per- resistance.
form surveillance activities. Program personnel should be in- 3. The long-term impact of formulary restriction and
cluded as active members on the hospital infection control and preauthorization requirements on antimicrobial use and
pharmacy and therapeutics committees or their equivalents. resistance.
Central to an effective program is a proactive strategy in- 4. Evaluation of “bundled” approaches that incorporate
corporating prospective audit with direct intervention and feed- many or all of the most effective strategies.
back to the provider and/or preauthorization requirements for 5. Examination of the effectiveness of these strategies in
antimicrobial use. On the basis of an understanding of local more detail in subpopulations of hospitalized patients, includ-
antimicrobial use and resistance problems and of available re- ing neonates, infants, and children; elderly patients; and severely
sources that may differ depending on the size of the institution, immunocompromised patients.
the core active strategies may be supplemented by education, 6. The ability of antimicrobials to cause “collateral dam-
guidelines and clinical pathways, antimicrobial order forms, age” or unintended ecological resistance, to focus interventions.
adequate empirical therapy followed by de-escalation based on 7. The incremental role of antimicrobial stewardship
culture results, dose optimization, and a systematic plan for combined with infection control practices, such as hand hy-
conversion from parenteral to oral therapy. Consensus building giene and isolation, designed to prevent secondary spread of
with the support of administration and local providers is es- resistant organisms.
sential, with the focus on collaborating in the safety and care 8. Understanding the resistance gene pool through mo-
of their patients rather than a policing role. Although reports lecular epidemiology, to determine the relative impact of an-
describing the clinical and economic impacts of multidisci- timicrobial stewardship and infection control practices on spe-
plinary antimicrobial management programs are limited to sin- cific resistant bacteria, to tailor an approach to local resistance
gle-center longitudinal studies, they consistently demonstrate issues.
a decrease in antimicrobial use (22%–36%) and annual savings 9. Development and validation of automated surveillance
of $200,000–$900,000, which more than pays for the program strategies for nosocomial infections and real-time monitoring
in both larger academic hospitals [2, 3, 5, 7, 8, 69] and smaller of resistance trends.
community hospitals [4, 6]. Quantifying a long-term impact 10. Development of decision-support systems incorpo-
on antimicrobial resistance has been more challenging, and rating antimicrobial stewardship into CPOE.

11. Development and cost-effectiveness of more rapid and antimicrobial agents in hospitals: a statement by the Infectious Dis-
eases Society of America. J Infect Dis 1988; 157:869–76.
sensitive diagnostic tests, to identify patients with bacterial ver- 10. Shlaes DM, Gerding DN, John JF, et al. Society for Healthcare Epi-
sus viral infections and to identify resistant bacterial organisms demiology of America and Infectious Diseases Society of America
earlier. joint committee on the prevention of antimicrobial resistance: guide-
lines for the prevention of antimicrobial resistance in hospitals. Clin
12. Strategies to stimulate research and development of
Infect Dis 1997; 25:584–99.
novel antimicrobials as outlined in the IDSA “Bad Bugs, No 11. Lawton RM, Fridkin SK, Gaynes RP, McGowan JE. Practices to im-
Drugs” campaign. prove antimicrobial use at 47 US hospitals: the status of the 1997
13. Education and training of infectious diseases fellows SHEA/IDSA position paper recommendations. Infect Control Hosp
Epidemiol 2000; 21:256–9.
and pharmacists in the area of antimicrobial stewardship, in- 12. Girouard S, Levine G, Goodrich K, et al. Infection control programs
cluding program implementation and management. at children’s hospitals: a description of structures and processes. Am
14. The influence of pharmaceutical industry and repre- J Infect Control 2001; 29:145–51.
13. Sunenshine RH, Liedtke LA, Jernigan DB, Strausbaugh LJ. Role of
sentatives on antimicrobial prescribing within the health care infectious disease consultants in management of antimicrobial use in
setting and effective strategies to counteract inappropriate hospitals. Clin Infect Dis 2004; 38:934–8.
detailing. 14. Burke JP. Infection control: a problem for patient safety. N Engl J
Med 2003; 348:651–6.
15. John JF, Fishman NO. Programmatic role of the infectious diseases
physician in controlling antimicrobial costs in the hospital. Clin Infect

Acknowledgments Dis 1997; 24:471–85.
16. Reimann HA. The misuse of antimicrobics. Med Clin North Am
We wish to express our gratitude to Ronald E. Polk, Christopher A. Ohl, 1961; 45:849–56.
and Joseph F. John, Jr., for their thoughtful reviews of this guideline. 17. Kislak JW, Eickhoff TC, Finland M. Hospital-acquired infections and
Potential conflicts of interest. J.E.M. has received research support for antibiotic usage in the Boston City Hospital—January, 1964. N Engl
Project ICARE from AstraZeneca, bioMérieux, Elan, Pfizer, and 3M Health J Med 1964; 271:834–5.
Care and has served as a consultant for Cubist, Dade Microscan, Merck, 18. Roberts AW, Visconti JA. The rational and irrational use of systemic
Replidyne, and Wyeth. D.N.G. has patents licensed to ViroPharma; has antimicrobial drugs. Am J Hosp Pharm 1972; 29:828–34.
received research grants from Genzyme, Massachusetts Biological Labo- 19. McGowan JE. Antimicrobial resistance in hospital organisms and its
ratories, and ViroPharma; and has served as consultant for AstraZeneca, relation to antibiotic use. Rev Infect Dis 1983; 5:1033–48.
Genzyme, Optimer, Romark, GOJO, Salix, and ViroPharma. W.C.H. has 20. Monroe S, Polk R. Antimicrobial use and bacterial resistance. Curr
received research support from Elan and Merck and has served as con- Opin Microbiol 2000; 3:496–501.
sultant to Roche Diagnostics. D.L.P. has received research grants from 21. Barbosa TM, Levy SB. The impact of antibiotic use on resistance
AstraZeneca, Elan, Merck, and Pfizer and has served as a consultant or on development and persistence. Drug Resistance Updates 2000; 3:
speakers’ bureaus for Merck, Cubist, Pfizer, Elan, and Genzyme. M.B. has 303–11.
served on speakers’ bureaus for Merck and Pfizer. All other authors: no 22. Paterson DL. “Collateral damage” from cephalosporin or quinolone
conflicts. antibiotic therapy. Clin Infect Dis 2004; 38(Suppl 4):S341–5.
23. Courcol RJ, Pinkas M, Martin GR. A seven year survey of antibiotic
susceptibility and its relationship with usage. J Antimicrob Chemother
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GUIDELINES

Infectious Diseases Society of America and the

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Category, grade Definition

NOTE. Adapted from [1].

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162 • CID 2007:44 (15 January) • Dellit et al.

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164 • CID 2007:44 (15 January) • Dellit et al.

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Antimicrobial Stewardship Guidelines • CID 2007:44 (15 January) • 165

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166 • CID 2007:44 (15 January) • Dellit et al.

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168 • CID 2007:44 (15 January) • Dellit et al.

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170 • CID 2007:44 (15 January) • Dellit et al.

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172 • CID 2007:44 (15 January) • Dellit et al.

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Antimicrobial Stewardship Guidelines • CID 2007:44 (15 January) • 173

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174 • CID 2007:44 (15 January) • Dellit et al.

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